Chest
Volume 145, Issue 2, February 2014, Pages 231-236
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Original Research: Pulmonary Vascular Disease: Featured
EIF2AK4 Mutations in Pulmonary Capillary Hemangiomatosis

https://doi.org/10.1378/chest.13-2366Get rights and content

Background

Pulmonary capillary hemangiomatosis (PCH) is a rare disease of capillary proliferation of unknown cause and with a high mortality. Families with multiple affected individuals with PCH suggest a heritable cause although the genetic etiology remains unknown.

Methods

We used exome sequencing to identify a candidate gene for PCH in a family with two affected brothers. We then screened 11 unrelated patients with familial (n = 1) or sporadic (n = 10) PCH for mutations.

Results

Using exome sequencing, we identified compound mutations in eukaryotic translation initiation factor 2 α kinase 4 (EIF2AK4) (formerly known as GCN2) in both affected brothers. Both parents and an unaffected sister were heterozygous carriers. In addition, we identified two EIF2AK4 mutations in each of two of 10 unrelated individuals with sporadic PCH. EIF2AK4 belongs to a family of kinases that regulate angiogenesis in response to cellular stress.

Conclusions

Mutations in EIF2AK4 are likely to cause autosomal-recessive PCH in familial and some nonfamilial cases.

Section snippets

Study Participants

All participants provided written informed consent for genetic studies according to protocols approved by the institutional review boards (IRBs) of the participating institutions (Columbia University IRB #AAAA8979 and #AAAC0884; Intermountain Healthcare Urban Central Region IRB #1007044; Vanderbilt University IRB #9401).

We diagnosed PCH in two male siblings in a family (Fig 1). In 2004, PCH was diagnosed in the first sibling (II.1) at 20 years of age at the time of lung transplantation.

Exome Sequencing

Through our filtering process, we identified a gene (EIF2AK4) containing two novel, clearly pathogenic mutations: c.1153dupG (p.Val385fs) and c.3766C>T (p.Arg1256X) shared by both affected brothers (Fig 1). Both variants were confirmed in each brother by Sanger sequencing. Both unaffected parents were heterozygous carriers of one of the two mutations in EIF2AK4. The mother carried the frameshift mutation, c.1153dupG, and the father carried the nonsense mutation, c.3766C>T. The unaffected sister

Discussion

We report the identification of a novel gene, EIF2AK4, as a likely cause of autosomal-recessive PCH characterized by proliferation of small pulmonary capillaries. Whole-exome sequencing allowed us to identify two loss-of-function mutations in EIF2AK4 by analyzing only two affected brothers with PCH. We confirmed the role of EIF2AK4 in PCH by identifying two of 10 additional patients with no family history of PCH, each with two clear loss-of-function mutations. Previous reports suggested an

Conclusions

In conclusion, we identified mutations in EIF2AK4 as a novel genetic cause of PCH for some familial and sporadic patients with PCH. This finding provides a new opportunity to advance our understanding of the pathogenesis of PCH and pulmonary vascular biology.

Acknowledgments

Author contributions: Drs Best, Brown, and Elliott had full access to all data in the study and take responsibility for the data and the accuracy of the data analysis.

Dr Best: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article; and revising it critically for important intellectual content.

Ms Sumner: contributed to conception and design; acquisition, analysis, and interpretation of data; drafting of the submitted article;

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Funding/Support: This research was supported in part by the National Institutes of Health [K23 HL098743; R01 HL060056; NIH 1P01HL108800-0] and Intermountain Research and Medical Foundation [1007044].

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